Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo
Open accessAbstract
Ascorbate (ascorbic acid, vitamin C), in pharmacologic concentrations easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacologic ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc(*-)) and H(2)O(2) in the extracellular space compared with blood. Here we test this hypothesis in vivo. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacologic doses ( approximately 0.25-0.5 mg per gram of body weight). After i.v. injection, ascorbate baseline concentrations of 50-100 microM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concentrations of <150 microM in both fluids. In blood, Asc(*-) concentrations measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concentrations were >8 mM. After parenteral dosing, Asc(*-) concentrations in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concentrations. By using the synthesized probe peroxyxanthone, H(2)O(2) in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc(*-) concentrations in extracellular fluid exceeded 100 nM. The data show that pharmacologic ascorbate is a prodrug for preferential steady-state formation of Asc(*-) and H(2)O(2) in the extracellular space but not blood. These data provide a foundation for pursuing pharmacologic ascorbate as a prooxidant therapeutic agent in cancer and infections.
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The plasma levels of dehydroascorbic acid are very low in healthy humans, while ascorbyl radical is undetectable.
“The plasma levels of dehydro-ascorbic acid are very low in healthy humans, while that of an ascorbyl radical are undetectable [6,53,54,62,67].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [67]
The Results (page unavailable) report that ascorbate radical was undetectable in rat blood after oral administration, but they do not establish that it is undetectable in the plasma of healthy humans. The passages on plasma concentrations concern ascorbate, not dehydroascorbic acid; a search for dehydroascorbate found no supporting measurement. (LLM, conf=0.86)
Experimental — accuracy not yet measuredVitamin C given intravenously increases the production of hydrogen peroxide dose-dependently in extracellular fluid but not in blood.
“It was shown that vitamin C given intravenously increases the production of hydrogen peroxide dose-dependently in extracellular fluid but not in blood.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [67]
In extracellular fluid, vitamin C concentrations are slightly higher than in plasma but generally reflect plasma levels.
“In extracellular fluid, the concentrations are slightly higher than in plasma, but, in general, they reflect plasma levels [67].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [67]
In rats given intravenous ascorbate at 0.5 g kg−1, ascorbate radical and H2O2 formed in vivo, with amounts depending on the ascorbate dose.
“Asc•− and H2O2 were generated in vivo following intravenous ascorbate injections in rats (0.5 g kg−1), and the production was ascorbate-dose-dependent35.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [35]
Pharmacological ascorbate acts as a prodrug that preferentially forms ascorbate radical and hydrogen peroxide in the extracellular space, but not in blood, in vivo.
“This study shows that pharmacological ascorbate is a prodrug for preferential steady-state formation of Asc•- and H2O2 in the extracellular space but not in the blood in vivo system.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [35]
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- Authors
- Chen, Q., Espey, M. G., Sun, A. Y., Lee, J.-H., Krishna, M. C., Shacter, E., Choyke, P. L., Pooput, C., Kirk, K. L., Buettner, G. R., & Levine, M.
- Affiliations
- National Institutes of Health (US)
- Radiation Biology Branch and the
- *Molecular and Clinical Nutrition Section and
- United States Food and Drug Administration (US)
- National Cancer Institute (US)
- University of Iowa (US)
- Corresponding author
- Levine, Mark
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-05-22
- Volume
- 104
- Issue
- 21
- Pages
- 8749-8754
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1885574
- OpenAlex
- W2140968862
- Cited by
- 676
- References
- 42
- Citations by year
- 2026: 21 · 2025: 35 · 2024: 25 · 2023: 39 · 2022: 44 · 2021: 52 · 2020: 49 · 2019: 49 · 2018: 48 · 2017: 42 · 2016: 34 · 2015: 36 · 2014: 29 · 2013: 33 · 2012: 30
- FWCI
- 21.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK054506)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- vitamin C, ascorbyl radical, hydrogen peroxide, pharmacologic ascorbate, prodrugs, extracellular fluid, blood, parenteral administration, oral administration, tumor cell killing, EPR detection
- MeSH terms
- Animals, Ascorbic Acid, Female, Free Radicals, Hydrogen Peroxide, Infusions, Parenteral, Male, Molecular Structure, Extracellular Fluid, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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